Globally, tobacco use accounts for 4.9 million deaths each year, including 400,000 in the U.S. These deaths are caused by inhaled smoke toxicants like carcinogens, carbon monoxide (CO), and nitric oxide (NO). Another smoke toxicant, nicotine, produces dependence with prolonged use. Cigarette smoke toxicant content and smoker toxicant exposure has been well characterized, as have the subjective and cardiovascular effects of cigarette smoking. However, in the U.S. and globally, millions of people use waterpipes (hookah or shisha) to smoke tobacco: the smoker fills the head with sweetened and flavored tobacco, covers it with perforated aluminum foil, and tops the foil with lit charcoal. Charcoal and tobacco smoke pass to the user via a half-filled water bowl, hose, and mouthpiece. Waterpipe tobacco smoking is increasing in the U.S., especially among college students for whom prevalence rates may be 15-20%. Relative to one cigarette, one waterpipe use episode can generate 100 times the smoke, with user toxicant exposure, effects, and smoke toxicant content that are largely unknown. These outcomes may depend upon an individual's use frequency and whether the individual uses the waterpipe alone or with a group. This project combines clinical laboratory methods, analytical chemistry, and cellular biology to achieve three specific aims. 1) Learn about individual waterpipe user toxicant exposure, effects, and smoke toxicant content. In two separate sessions, 130 waterpipe users (65 reporting 2-5 uses/month and 65 reporting > 21 uses/month) will use a waterpipe loaded with preferred brand/flavor of waterpipe tobacco or placebo. Outcome measures include CO and NO, plasma nicotine, subjective, cardiovascular, and pulmonary response, and puff topography (puff number, volume, duration, and interpuff interval). Topography records will be replayed in an analytical laboratory to study smoke toxicant content and cytotoxicity/mutagenicity. 2) Learn how group use influences waterpipe toxicant exposure, effect, and smoke toxicant content. In an observational study, trained staff will use rigorous sampling and data collection procedures to study group waterpipe tobacco smoking in local cafs. In a laboratory study informed by observational study results, 65 waterpipe- sharing groups will use a waterpipe in the laboratory as a group in one session, and as individuals in another session, and user toxicant exposure and effects, and smoke toxicant content will be assessed as in Study 1. 3) Compare the toxicant exposure and effects of waterpipe tobacco smoking and cigarette smoking. In two sessions, 100 waterpipe users who also smoke cigarettes will either use a waterpipe or smoke a cigarette; outcome measures include exposure to CO, NO, and nicotine, as well as cardiovascular, respiratory, and subjective effects. Waterpipe use is disturbingly common among U.S. young adults. More information is needed about waterpipe effects, and it can be obtained from clinical laboratory studies and smoke toxicant analysis. This information is necessary to understand this potentially dangerous behavior, while shaping knowledge, opinions, and attitudes in a way that enhances public health. This project is relevant to public health because waterpipe tobacco smoking is a little-understood but rapidly emerging strain in the nation's tobacco use epidemic. The project will inform nascent efforts to prevent waterpipe tobacco smoking from contributing substantially to tobacco's morbidity and mortality by revealing the user toxicant exposure, subjective, cardiovascular, and pulmonary effects, and cytogenicity and mutagenicity of waterpipe tobacco smoke produced by individuals and groups; it will also address frequent but probably erroneous statements regarding waterpipe filtering and lower toxicant levels relative to cigarette smoke. The positive health impact of this type of research on tobacco cigarette smoking is well-documented; this project seeks similar positive outcomes on another potentially lethal form of tobacco use. This project is relevant to public health because waterpipe tobacco smoking is a little-understood but rapidly emerging strain in the nation's tobacco use epidemic. The project will inform nascent efforts to prevent waterpipe tobacco smoking from contributing substantially to tobacco's morbidity and mortality by revealing the user toxicant exposure, subjective, cardiovascular, and pulmonary effects, and cytogenicity and mutagenicity of waterpipe tobacco smoke produced by individuals and groups; it will also address frequent but probably erroneous statements regarding waterpipe filtering and lower toxicant levels relative to cigarette smoke. The positive health impact of this type of research on tobacco cigarette smoking is well-documented; this project seeks similar positive outcomes on another potentially lethal form of tobacco use.